Skin cancer is the most common class of malignancy in humans. In the United States, there are over 1.5 million cases of skin cancer a year, including those of keratinocytic origin such as basal cell and squamous cell carcinoma, and melanoma. It is well known that the behavior of skin cancer, most notably squamous cell carcinoma (SCC), is markedly affected by the immune status of patients. Iatrogenically immunosuppressed patients, such as organ transplant recipients, have a 65-250-fold higher risk of SCC relative to non- immunosuppressed individuals. Evidence from multiple human cancers demonstrates that inflammation from chronic injury or infection has potent tumor-promoting effects. Evidence from model systems indicates that some subpopulations of T-cells and B-cells have differing effects on tumor growth. Given the evidence that immune responses can aggravate and inhibit tumor growth, there is a critical need to investigate the roles of the immune system in the initiation, development, and treatment of skin cancer. Such an understanding has the potential to inform directed use of the immune system to destroy tumors and also has the potential to separate the beneficial effects of immunosuppressive medications from tumor-promoting ones. Our long-term goal is to develop novel and effective therapeutic strategies for cancer based upon targeted manipulation of the immune system. The objective of this application is to validate a transplantable squamous cell carcinoma model in mouse that permits independent manipulation of the tumor, drug-induced immunosuppression, and the host immune system. Our central hypothesis is that drug-induced immunosuppression will increase the aggressiveness of implanted squamous cell carcinoma by altering the balance of T-cell subsets that infiltrate the tumor. The rationale for these studies is that the identification of key mediators of immune-system - tumor interactions will firmly establish a framework through which immune modulators may be tailored for cancer therapy. Our research team includes experts in mouse models of cancer, antigen presenting cell (APC) - T-cell interactions, as well as immunosuppression in skin cancer. We aim to (1) create and validate a clinically-relevant mouse model of SCC for studies of cancer immunology in immunosuppressed mice by combining an immunogenic transplantable SCC model with exogenous immunosuppression and (2) identify in real-time, the contribution of immune cell subsets, in particular T- regulatory cells, to tumor implantation and growth in vivo. PUBLIC HEALTH RELEVANCE: The critical importance of the immune system in controlling skin cancer, particularly squamous cell carcinomas, has been convincingly demonstrated in the context of human patients, associated ultraviolet light-induced and drug-induced immunosuppression, and in the emerging and often conflicting roles of inflammation and cancer. There is an urgent need to better understand tumor - host-immune system interactions so directed use of the immune system for cancer therapy can be further advanced. We aim to develop a modular model of immunosurveillance in immunocompetent mice that will enable the independent manipulation of tumor cells and the host immune system so that mechanistic insights and therapeutic interventions may be more readily developed.